The purpose of this grant is to bring a variety of scientific disciplines to bear on a number of specific drug abuse problems. We propose to carry out major projects in the areas of narcotic agonists and antagonists, the active principles of marihuana, sedatives and hypnotics and methodology development. In the area of narcotics and narcotic antagonists, we plan extensive studies ranging from synthetic chemistry to behavior in order to shed some light on the stereospecificity and mechanism of action of these compounds. Specific projects include characterization of the putative sigma and "cough" receptors. Studies will include general pharmacology , dependence evaluation, drug discrimination and receptor binding. Our studies with the cannabinoids will involve metabolic fate and distribution; attempts to characterize central sites of action, evaluation of the possible "behavioral" dependence; interactions with other drugs; and the mechanism of their antinauseant activity. In the sedative-hypnotics, minor tranquilizer area, we propose to develop simple inexpensive methods for assessing their dependence liability. We will continue our mechanistic studies focusing on a recently described benzodiazepine antagonist. We propose to use this antagonist as a tool to ascertain whether there are real mechanistic differences between the mild tranquilizer and the barbiturates.